Glutarimides for reducing the number of fetuses in mated or impregnated female mammals

ABSTRACT

PHARMACEUTICAL COMPOSITIONS COMPRISING AN EFFECTIVE AMOUNT OF AN A-(4-AMINOPHENYL)-A-LOWER ALKYL-GLUTARIMIDE, A SALT OR N-LOWER ALKANOYL DERIVATIVE THEREOF AND A PHARMACEUTICAL EXCIPIENT, ARE AGENTS FOR REDUCING THE NUMBER OF FETUSES IN MATED OR IMPREGNATED FEMALE MAMMALS.

United States Patent O GLUTARIMIDES FOR REDUCING THE NUMBER OF FETUSES IN MATED OR IMPREGNATED FEMALE MAMMALS Bernard George Steinetz, In, Mountain Lakes, N.J., assignor to Ciba-Geigy Corporation, Ardsley, N.Y. No Drawing. Filed June 1, 1971, Ser. No. 149,025

Int. Cl. A61k 27/00 US. Cl. 424-268 3 Claims ABSTRACT OF THE DISCLOSURE Pharmaceutical compositions comprising an effective amount of an a-(4-aminophenyl)-u-lower alkyl glutarimide, a salt or N-lower alkanoyl derivative thereof and a pharmaceutical excipient, are agents for reducing the number of fetuses in mated or impregnated female mammals.

BACKGROUND OF THE INVENTION Of the a-(4 aminophenyD- -loWer alkyl-glutarimides disclosed in US. Pat. No. 2,848,455, the u-ethyl derivative, i.e. aminoglutethimide, has already been used at low dosage levels, e.g. in the form of 125 and 250 mg. tablets, as a long-term anticonvulsant which, alone or particularly as an adjunct, controls seizures in most forms of epilepsy, even in cases refractory to other therapeutic agents. Surprisingly, it was found that said glutarimides exert at higher dosage levels, but applied in a much shorter period of time, a fetal reducing effect in female mammals, which is not accompanied by the alleged adverse sideeffects described for the long-term treatment.

SUMMARY OF THE INVENTION The present invention concerns and has for its object the provision of a pharmaceutical composition comprising essentially (a) an effective amount of a compound corresponding to Formula I NHX N in which R is lower alkyl and X is hydrogen or lower alkanoyl, or a therapeutically acceptable acid addition salt thereof, and (b) a pharmaceutical excipient; as well as of a new method of reducing the number of fetuses in mated or impregnated female mammals with said active compounds of Formula I, advantageously in the form of orally applicable pharmaceutical compositions thereof.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The active ingredients of the compositions claimed herein are described in US. Pat. No. 2,848,455. Preferred is the a-(4-aminophenyl) a ethyl-glutarimide (aminoglutethimide). Said ingredients can be used in the free form or in the form of therapeutically acceptable acid addition salts thereof. Preferred salts are those of inorganic acids, e.g. hydrochloric, hydrobromic, sulfuric, nitric, perchloric or especially phosphoric acid, but also those of organic acids, such as carboxylic or sulfonic acids, e.g. formic, acetic, propionic, succinic, glycollic, lactic, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, pyroracemic, phenylacetic, benzoic, 4 aminobenzoic, anthranilic, 4-hydroxybenzoic, salicylic, aminosalicylic, embonic, nicotinic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, ethylenesulfonic, benzenesulfonic, halogenbenzenesulfonic, toluenesulfonic, naphthalenesul- 3,836,659 Patented Sept. 17, 1974 fonic or sulfanilic acid, methionine, tryptophan, lysine or arginine.

The compositions according to the invention are applied to female mammals at a dosage level corresponding to about 20 to about 200 mg./kg. of said glutarimides, preferably between about 50 and 150 (mg/kg, per day or 8-16 hour period, either in a single or advantageously in multiple dosage units from preferably two to three times, up to about four to six times, either prior or after conception, for example, during the first quarter of gestation.

Said properties of the compositions according to this invention can be demonstrated, for example, in animal tests, using mammals, e.g. rats, hamsters or rabbits, as test objects. Such tests can be performed by administering said active glutarimides in the form of aqueous solutions or suspensions by stomach tube to said test animals at any of the first 9 days of pregnancy in a dosage range between about 20 and 200 mg./kg./day, or preferably 8 hours, in up to 3 consecutive doses. On day 11 the animals are sacrificed and their uterus compared with that of control animals. Thus, for example, when a composition of aminoglutethimide, the characteristic compound of the compositions according to this invention, is administered in the above manner orally or subcutaneously as a simple or acetate-buffered aqueous solution of the phosphate thereof, to rats at one to three consecutive dosages of about to 200, preferably mg./kg./8- 24 hours, following the 9th day of pregnancy, no or very few fetuses are found in the uterus of the medicated animals, as compared with an average of 11 found in that of the control animals. In another test system, using rabbits, a single dose of an aqueous aminoglutethimide phosphate solution of about 100 mg./kg., markedly reduced the secretion of progesterone by the ovary. This is estimated by the continuous withdrawal of blood from the ovarian vein, starting about /2 hour prior to drug administration and continuing for a total of 1 /2 hour. During this time, the blood-progesterone content is monitored by standard methods and falls to a level below 50% of the control value. Similar results are obtained from either pregnant or non-pregnant animals.

Accordingly, said compositions of the invention are enterally or parenterally, advantageously orally applicable agents. Preferred are tablets and gelatin capsules comprising the active ingredient together with (a) diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine, (b) lubricants, e.g. silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol, for tablets also (c) binders, e.g. magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, if desired, (d) disintegrants, e.g. starches, agar, alginic acid or its sodium salt, enzymes of the binders or effervescent mixtures and/or (e) adsorbents, colorants, flavors and sweeteners. Injectable compositions are preferably aqueous isotonic solutions or suspensions, and suppositories are advantageously fatty emulsions or suspensions. They may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. Said pharmaceutical compositions may also contain other therapeutically valuable substances. They are prepared according to conventional mixing, granulating or coating methods respectively, and contain about 10 to 90%, preferably about 20 to 80%, of the active ingredient, or advantageously about 0.5 to l g. thereof per dosage unit.

The method of treatment according to the invention consists in administering to a mated or impregnated female mammal a single, or preferably multiple dose of about 20 to about 200 rag/kg. preferably about 50 to about 150 mg./kg./8-24 hours of said active a-(4-aminophenyl)-ulower alkylglutarimide, its lower alkanoyl derivative or salt, preferably in the form of the above compositions, advantageously in an orally applicable form, e.g. as tablet, drage or capsule and advantageously during the first quarter of gestation. For a mammal of about 50 to 70 kg. weight, the administration of about 1 to 2 g. of said glutarimides, especially aminoglutethimide, in single or multiple oral dosage units is preferred. For example, 500 mg. tablets or capsules of aminoglutethimide can be administered to said mated female mammal up to four times during a period of 1.5 to 4 days, in order to reduce the number of fetuses.

The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon.

EXAMPLE 1 Preparation of 1,000 tablets, each containing 500 mg of the active ingredient:

Formula: G. Aminoglutethimide 500.0 Lactose 240.0 67% aqueous sucrose 45.0 Talcum 20.0 Stearic acid 5.0 Magnesium stearate 5.0

EXAMPLE 2 Preparation of 1,000 tablets, each containing 0.5 or 1 g. of the active ingredient:

Grams Formula:

Aminoglutethimide 500. 1, 000. 0 Wheat starch 140. 0 200. 0 Methylcellulose,

14. 0 20. 0 7. 0 10. 0 32. 0 55. 0 7. 0 15. 0 Purified waterq.s.

Procedure: All the powders are passed through a screen with 0.6 mm. openings. Then the drug substance, methylcellulose and silica are mixed well and granulated with a paste of the starch and about 5-6 times the amount of water. The granulate is dried overnight at 35, broken on a screen with 1.2 mm. openings, mixed with the talcum and stearic acid and compressed into 12 mm. or capsuleshaped tablets, respectively.

What is claimed is:

1. A method of reducing the number of fetuses in a female mammal, which consists in the administering to a mated or impregnated female mammal a single or multiple enteral or parenteral dose of about 20 to about 200 mg. of a compound corresponding to the formula Q lO -NH2 References Cited UNITED STATES PATENTS 2,848,455 8/1958 Hoifmann et a1 260281 OTHER REFERENCES Hospital Formulary, American Society of Hospital Pharmacists, Washington, D.C., April 1961, Amino- Glutethimide Entry.

Stedmans Medical Dictionary, 22nd ed., The Williams & Wilkins Company, Baltimore, Md. (1972), pp. 458, 460 and 1224 (.Fecundate, Fertile and Suppression Entries).

ALBERT T. MEYERS, Primary Examiner V. C. CLARKE, Assistant Examiner U.S. Cl. X.R. 424--267, 3 6 l 

